Novel 3.alpha.-(Diphenylmethoxy)tropane Analogs: Potent Dopamine Uptake Inhibitors without Cocaine-like Behavioral Profiles

Journal of Medicinal Chemistry
1994.0

Abstract

We synthesized a series of 4'-substituted 3a-(diphenylmethoxy)tropane analogs to investigate their potential as novel dopamine uptake inhibitors and evaluate their pharmacological and behavioral properties. The analogs were prepared by reacting para-substituted benzhydryl chlorides with tropine at 160°C and isolated as hydrochloride salts. Their affinity for the dopamine transporter was determined via displacement of [³H]WIN 35,428 binding in rat caudate-putamen, and their inhibition of [³H]dopamine uptake was measured. Behavioral assessments included locomotor activity in mice and substitution for cocaine in rats trained to discriminate cocaine from saline. Most analogs exhibited greater potency than the parent compound benztropine (2) in both binding and uptake inhibition, with the 4',4''-difluoro analog (7c) being the most potent. The 3β-diastereomer (10) showed a ~30-fold reduction in potency compared to its 3α-counterpart (7a). Importantly, compound 7a, despite its high affinity for the dopamine transporter, demonstrated reduced locomotor stimulant efficacy relative to cocaine and failed to substitute for cocaine in the discrimination assay. This study identifies 7a as the first tropane analog structurally related to cocaine and GBR 12909 that combines high-affinity dopamine transporter binding and dopamine uptake inhibition with a behavioral profile distinct from cocaine, suggesting its potential as a candidate for cocaine antagonist development.

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